Existing methods for preparing 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole are limited by the excessive cost of commercial scale application of laboratory procedures. Many existing reports are based on laboratory studies and thus present little information on how reaction conditions and particular reactants would affect product yield or purity. In addition, use of procedures and reactions developed in the laboratory cannot be directly applied to commercial scale production because such laboratory procedures typically involve the use of expensive reactants and/or expensive (e.g., separation and purification procedures) techniques.
U.S. Pat. No. 3,562,284 discloses a process for making certain 2-(alkylthio)-5-(halogenoalkyl)-1,3,4-thiadiazoles such as 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazoles wherein methyldithiocarbazinate is reacted with a carboxylic anhydride (e.g., trifluoroacetic anhydride) or with a carboxylic acid (e.g., trifluoroacetic acid) in a solvent (e.g., toluene). The reaction can occur in the presence of phosphorous trichloride and pyridine with added sulfuric acid (DE-A-3,422,861) or with carbonyl chlorides (e.g., trifluoroacetyl chloride) and diethylene glycol dimethyl ether, as well as pyridine and sulfuric acid (DE-A-3,722,320).
The first-mentioned method is poorly suited for commercial, large-scale production because the reactants (anhydrides) are expensive and they are used in excess. In addition, by using an anhydride, only half of the reaction moiety is utilized. The reaction with carboxylic acids, phosphorus trichloride, pyridine, sulfuric acid and carbonyl chlorides requires an extensive work-up procedure in which the pyridine is separated off and recovered. Further, phosphorus trichloride forms only sparingly soluble reaction products, which makes mixing difficult and produces unacceptable amounts of waste. Finally, the yields realized from such processes are unacceptably low.
Other procedures for making a 2-(substituted)-5-(trifluoromethyl)-1,3,4-thiadiazole involve the reaction of a carboxylic acid (e.g., trifluoroacetic acid) and a dithiocarbazic ester in the presence of a phosphorylchloride or polyphosphoric acid. (See, e.g., U.S. Pat. No. 5,162,539 and Gyoefi and Csavassy, Acta Chimica Academiae Scientiarum Hungaricae, Tomus 82 (1): 91-97, 1974). The use of such phosphorus compounds results in the formation of waste products containing unacceptably high levels of phosphates and, thus, creates an environmental hazard. Still further, this method requires the use of dry methyldithiocarbazinates (a toxic convulsant). In the dry state this material creates a severe industrial hygiene problem.
There is a need in the art, therefore, for an efficient, high yield, practical, safe method for the commercial, large-scale production of 2-(methylthio)-5-(trifluoromethyl)-1,3,4-thiadiazole. The present invention provides such a process.